Integration of molecular cancer classification and NGS to identify metastatic patients eligible for IDH inhibitors.

647 Background: Mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2) often occur in hematologic malignancies and solid tumors. Ivosidenib was recently approved for IDH1-mutated cholangiocarcinoma based on improved progression-free survival (PFS) and overall survival (OS). Notably, cancers of uncertain diagnoses presenting as liver metastases are often cholangiocarcinoma. While several trials are ongoing to evaluate IDH1/2 inhibitor efficacy in other advanced solid tumor types, currently eligibility for IDH inhibitor therapy requires both tumor type identification and IDH mutation confirmation. The 92-gene assay (CancerTYPE ID) is a gene expression classifier of 50 tumor types and subtypes for metastatic patients with diagnostic ambiguity. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. Here, a database of metastatic cases that integrates tumor type with biomarker analysis was used to identify those eligible for IDH inhibitor treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tumor type-guided multimodal biomarker testing by NGS (Neogenomics). In this study, metastatic cancers classified as pancreaticobiliary and other solid tumor types with IDH1/2 mutations were identified. Results: CancerTYPE ID determined 27 different tumor types in 2377 of 2572 cases (92.4%). The most common tumor type identified was pancreaticobiliary with 644 cases; subtypes with IDH1/2 mutation status are shown in the table. An IDH1 mutation was identified in 23 out of 78 (29.5%) cholangiocarcinoma cases which are eligible for ivosidenib treatment. IDH1/2 mutations were also detected in 11 other tumor types. For patients with IDH1 mutations, 28.2% were identified in tumor types with no FDA-approved IDH therapy, whereas 50.0% of IDH2 mutations overlapped with tumor types that have ongoing trials to determine the clinical benefit of targeting IDH2. Conclusions: These findings support the clinical utility of molecular tumor type classification combined with biomarker profiling to identify approved or investigational treatment options. The MOSAIC analysis identified metastatic patients with actionable aberrations ( IDH1) eligible for FDA-approved therapy, as well as those who may be eligible for investigational IDH inhibitor therapies based on tumor type and IDH1/2 mutation status. As new and approved IDH inhibitors are evaluated for efficacy, increased patient selection may be afforded through this approach in additional tumor types.[Table: see text]